L-Ascorbic acid, widely known in its generic name Vitamin C, is used in pharmaceuticals, food additives and cosmetics. It is widely used in connection with its antioxidative properties. The formulation of pure vitamin C into an end product, however, is difficult since it is oxidized easily, especially in aerobic conditions and upon light exposure. Therefore, rather than using ascorbic acid in its pure form, typically its derivatives are used. Ascorbic acid in its lactone form has four hydroxyl groups at carbons 2, 3, 5 and 6. These hydroxyl groups have different chemical activity. The 2- and 3-hydroxyl groups form an enediol system together with the double bond connecting carbons 2 and 3, which is very sensitive to oxidation. This system accounts to the oxidative degradation of ascorbic acid. The 5- and 6-hydroxyl groups on the other hand form a rather stable diol system. Common derivatization of ascorbic acid converts the hydroxyls to alkyl, acyl, sulfo or phospho-containing groups, which also influence the solubility of ascorbic acid in water or in oils. Known ascorbic acid derivatives fall into two main groups: water-soluble and oil-soluble ascorbic acid derivatives. These two groups differ in their potential use.
Widely used topical formulations contain 6-ascorbyl palmitate or stearate, fatty acid esters and thus have lipophilic properties and 2- or 3-magnesium ascorbyl phosphate, inorganic water-soluble acid esters. The enediol system of 6-ascorbyl palmitate is unprotected and this derivative is unstable in aqueous systems. It also has a rather limited solubility in water, oils and solvents commonly used in topical formulations. The enediol systems with the 2- or 3-ascorbyl phosphates and 2,3-di-O-acylates are relatively protected but may also become oxidized. Furthermore, they usually have to be produced in their polar, salt form, which is not compatible for skin formulations.
It was hitherto found that ascorbic acid and its derivatives up-regulate expression of procollagen genes in cultured dermal fibroblasts. It is well known that the collagen and elastin syntheses are mediated through lipoperoxides or their oxidative responses. The products of oxidation of ascorbic acid glycate proteins and rapidly produce protein-bound adducts and protein cross-links. The rate of glycation depends on oxidation rate of ascorbic acid in tissue. It is very important that oxidation begins only after penetration into stratum corneum, but not earlier. This means that ascorbic acid must be derivatized in order to prevent early oxidation. In this case ascorbic acid and its derivatives are able to stimulate collagen and elastin syntheses and significantly improve the condition of epidermis as well as corium of the skin tissue.
In recent years significant steps have been made to introduce vitamins and other active agents into dermatological or cosmetic compositions. These compositions may be used for specific treatments of various skin problems such as aging, dryness, acne or pigmentation disorders. Vitamin C incorporated into various compositions has to be strongly protected against oxidation by formulation, storage when formulated and by skin treatment.
EP 306,904 describes another approach in the field of vitamin formulation, involving binding of vitamin derivatives to a carrier. An example for a carrier is phosphoric acid to which two vitamin derivatives are bound, e.g. an ascorbic acid derivative and a tocopherol derivative, yielding an anti-oxidant composition. However, in this bi-vitamin form, the vitamin derivatives display a lower efficacy than in a free form. U.S. Pat. No. 5,098,898 describes the coupling of glycerol ester or ether to L-ascorbic acid via a phosphoric acid residue. The resulting compound exhibits good antioxidant activity as well as lipid peroxide inhibiting activity. However the enediol system is not adequately protected and thus cannot be used as a source of vitamin C in topical formulations.
JP 63,104,971 and DE 3,613,590 disclose synthesis of 2,3-di-O-acyl L-ascorbic acids, which are more photostable than above-mentioned phosphorylated L-ascorbic acids. However, 2,3-di-O-acylation leads to the loss of a biological activity and bioaccessibility because the low solubility of product in water. Therefore, such compounds are practically useless for cosmetic, dermatological and other applications.
JP 7,017,989, JP 8,034,791, JP 98,363,316 and JP 98,201,242 disclose applications of L-ascorbyl-2-phosphate in chemical peeling and skin-whitening compositions to prevent penetration of the agents to skin in depth and reduce skin irritation. 2-Phosphate containing derivatives of L-ascorbic acid show appropriate stability and preserve own activity.
U.S. Pat. No. 3,671,549 and DE 1,805,958 disclose synthesis of L-ascorbyl-3-phosphate by direct phosphorylation of ascorbic acid with a phosphorus halide, phosphoric and halophosphoric acids and corresponding anhydrides. The process is suitable for large-scale use.
JP 10,324,627 discloses synthesis of the L-ascorbic acid derivatives having phosphate, pyrophosphate, triphosphate, polyphosphate, sulfate, or glycosyl groups in position 2, and OH, phosphate, polyphosphate, sulfate, glycosyl, alkoxyl, alkenyloxyl, or phenoxyl groups in position 3, for their application as antitumor drugs. The problem of stability was not an aim of this patent but the new pharmacological activity only. Therefore position 2 was not o-substituted with the residue effective enough for the oxidative protection of the enediol double bond.